Sleep influences on homeostatic functions: implications for sudden infant death syndrome

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Abstract

The mechanisms underlying the sudden infant death syndrome (SIDS) appear to have origins in the fetal environment resulting in neural damage which later compromises responses to breathing or blood pressure challenges during sleep. The deficits appear to involve alterations in neurotransmitter receptors within regions involved in chemoreception and cardiovascular control. SIDS risk is enhanced by pre- and postnatal nicotine exposure, and possibly by hypoxic experiences. The prone sleeping position plays a significant role in risk, as do head positions that minimize facial escape from enclosed spaces; elevated body temperature may also be a factor. Compensatory mechanisms, including diminished gasping ability, relative failure to arouse to a safer state, or a failure to recruit respiratory efforts to overcome a blood pressure loss have been the object of recent research efforts. The findings suggest that the fatal event involves a neurally-compromised infant, circumstances that challenge vital physiology, most likely during sleep, at a particular developmental period.

Introduction

Infants who later succumb to the sudden infant death syndrome (SIDS), although exhibiting no major signs of physiological distress, show a variety of altered state-related respiratory, cardiovascular and arousal characteristics prior to death. Some of these patterns are manifest shortly after birth, suggesting deficits originating in fetal life. Epidemiologic evidence of enhanced risk from prenatal exposure to tobacco use (Sawczenko and Fleming, 1996) and maternal anemia (Bulterys et al., 1990) also supports the hypothesis that damage early in development underlies risk for the syndrome. That possibility does not exclude the potential that specific postnatal environmental conditions, e.g. second-hand smoking, overheating, airway obstruction, etc., may act in concert with existing deficiencies to further enhance risk for a fatal event.

The approaches to determining the mechanisms of death in SIDS are multifaceted, and include the identification of neural sites recruited in response to breathing and cardiovascular challenges, deficient anatomic sites in infants who have succumbed, and physiological characteristics of infants exposed to homeostatic challenges during sleep. The latter issue is of particular interest, because appropriate responses to a breathing or cardiovascular challenge within sleep may necessitate a state change or arousal, and deficiencies within state-switching mechanisms must be explored, in addition to systems which regulate routine breathing or cardiac patterns.

Section snippets

Neurotransmitters: the role of acetylcholine and nicotinic receptor binding

Among the risk factors for SIDS, prime consideration must be given to the role of nicotine exposure. Both pre- and postnatal exposure substantially increases the risk for SIDS, with a remarkable dose-dependent risk increase with postnatal exposure. The mechanism operating with nicotine exposure is obscure; however, preliminary evidence suggests that, compared to controls, infants with prenatal exposure who later succumb show a failure to up-regulate nicotinic binding in defined brainstem areas

Sleeping position

Any discussion of mechanisms operative in SIDS must account for the enhanced risk for SIDS from the prone position (Fleming et al., 1990, Ponsonby et al., 1993). Several pathophysiological mechanisms could underlie the enhanced risk. These mechanisms include rebreathing of expired gases and suffocation from facial proximity to bedding (Kemp and Thach, 1991, Bolton et al., 1993, Kemp et al., 1993), enhanced arousal thresholds in the prone position (Franco et al., 1996, Franco et al., 1998) which

Thermal and other sleeping environment considerations

In the prone position, the infant is potentially at greater risk from the adverse effects of heat stress from a warm environment, or, more importantly, from heavy wrapping (Fleming et al., 1993, Tuffnell et al., 1995). In the supine position, the adverse effects of heavy wrapping are less important than in the prone position, unless the head is completely covered (Fleming et al., 1996). SIDS victims are found to have been more heavily wrapped than controls, and the homes are more likely to have

Arousal

Infants at risk for SIDS show a relative inability to arouse to afferent stimuli (Newman et al., 1989), and infants who later succumb tend to remain asleep in the early morning hours; i.e. the normal momentary arousals which emerge as infants pass from one sleep state to another, occur less frequently (Schechtman et al., 1992b). The prone sleeping position raises the arousal threshold (Franco et al., 1996, Franco et al., 1998). Thus, ventilatory or other challenges, to which the normal

Antecedent physiologic signs

Physiologic patterns found prior to death in SIDS infants indicate subtle disturbances; however, these differences are small, and require careful partitioning of state, time-of-day, and age for detection. The differences include a relatively fixed breathing pattern during sleep, with a diminution of the normal occurrences of short apnea (Schechtman et al., 1991), periods of tachycardia, and less pronounced changes in heart rate that normally accompany inspiration and expiration (Kluge et al.,

Potential for cardiovascular failure

Evidence from several sources (Meny et al., 1994, Fox et al., 1996) indicates that some infants who succumb while on monitors can show a sudden-onset, profound bradycardia while breathing movements continue and, in some subjects, continued heart rate slowing, even if ventilation is supported. As loss of perfusion continues, gasping efforts may emerge. Thus far, the sleep state in which the fatal sequence occurs is uncertain, and interpretation of the patterns is made difficult by sparse data

Neural sites

Multiple neural sites mediate respiratory/blood pressure compensatory interactions. Some of the sites are well described, but other interactions remain obscure. The peripheral aortic and carotid blood pressure sensors, afferent projections to the nucleus of the solitary tract, and projections from the dorsal medulla to ventral medullary areas have been well described. Other interactions between somatic musculature and vestibular sensory transducers, acting in coordination with breathing action

Gasping, eupnea and autoresuscitation

The pattern of heart rate and breathing variability in infants who later succumb suggests deficits in eupnea and routine cardiac patterning. Considerable evidence exists that neural areas controlling eupnea differ from those mediating autoresuscitative responses, such as gasping (Fung et al., 1994, St. John, 1996), although localizing the particular structures involved in eupnea versus gasping is controversial (Ramirez et al., 1998). When hypoxia and/or hypotension are sufficiently severe to

Experiments of nature

To determine neural areas which mediate cardiovascular and breathing control, it is often useful to turn to pathology. Children with Congenital Central Hypoventilation Syndrome (CCHS) show a loss of breathing drive during sleep and a failure of appropriate respiratory responses to central chemoreception, although peripheral chemoreception appears to remain at least partially intact (Gozal et al., 1993). The physiological characteristics of these patients provide useful models to assess

Summary

The findings suggest that neural deficits in particular regions, or a developmental delay in particular systems, underlie the fatal event in SIDS. The evidence from the prenatal environment suggests that the neural handicap is established in fetal life, although the precipitating event during the fatal sequence may result from a unique set of circumstances in the compromised infant during a critical developmental period (Filiano and Kinney, 1993). Continuing postnatal neural damage from

Acknowledgements

Supported by RO1-HD-22506, RO1-HL-22418 and P50-HL-60296 (RMH), the SIDS Alliance, RO1-HD-20991 and PO1-HD36379 (KCH), RO1-HD-10993 (BBT), the Foundation for the Study of Infant Deaths, and the US National Institutes of Health (PJF).

References (74)

  • D.P. Bolton et al.

    Rebreathing expired gases from bedding: a cause of cot death?

    Arch. Dis. Child.

    (1993)
  • M.G. Bulterys et al.

    Chronic fetal hypoxia and sudden infant death syndrome: interaction between maternal smoking and low hematocrit during pregnancy

    Pediatrics

    (1990)
  • C.H. Chen et al.

    Cerebellar lesions alter autonomic responses to transient isovolaemic changes in arterial pressure in anaesthetized cats

    Clin. Auton. Res.

    (1994)
  • M.J. Coleman et al.

    Powerful depressed sympathoinhibitory effects evoked from neurons in the caudal raphe pallidus and obscurus

    Am. J. Physiol.

    (1995)
  • P. Deshpande et al.

    Failure of the autoresuscitation mechanism in weanling mice: significance of cardiac glycogen and heart rate regulation

    J. Appl. Physiol.

    (1999)
  • W. Dietrich et al.

    Effects of normothermic versus mild hyperthermic forebrain ischaemia in rats

    Stroke

    (1990)
  • A. Douglas et al.

    Seasonality and the sudden infant death syndrome during 1987–9 and 1991–3 in Australia and Britain

    Br. Med. J.

    (1996)
  • J.J. Filiano et al.

    Candidate cell populations for respiratory chemosensitive fields in the human infant medulla

    J. Comp. Neurol.

    (1990)
  • J.J. Filiano et al.

    A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model

    Biol. Neonate

    (1993)
  • P.J. Fleming et al.

    The interaction between bedding and sleeping position in sudden infant death syndrome: a population-based case-control study

    Br. Med. J.

    (1990)
  • P.J. Fleming et al.

    The development of thermoregulation and interactions with the control of respiration in infants: possible relationship to sudden infant death

    Acta Paediatr. Scand. Suppl.

    (1993)
  • P.J. Fleming et al.

    The environment of infants during sleep and the risk of sudden infant death syndrome: results of 1993–5 case-control study for confidential enquiry into stillbirths and deaths in infancy

    Br. Med. J.

    (1996)
  • Fox, G.P.P., Ledwidge, M.E., Matthews, T.G., 1996. Respiratory and autonomic function in the sudden infant death...
  • P. Franco et al.

    Decreased cardiac responses to auditory stimulation during prone sleep

    Pediatrics

    (1996)
  • M.L. Fung et al.

    Medullary loci critical for expression of gasping in adult rats

    J. Physiol. Lond.

    (1994)
  • B.C. Galland et al.

    The micro-environment of the sleeping newborn piglet covered by bedclothes: gas exchange and temperature

    J. Paediatr. Child Health

    (1994)
  • W.M. Gershan et al.

    Maturation of cardiorespiratory interactions in spontaneous recovery from hypoxic apnea (autoresuscitation)

    J. Pediatr. Res.

    (1990)
  • R. Gilbert et al.

    Combined effect of infection and heavy wrapping on risk of sudden unexplained infant death

    Arch. Dis. Child.

    (1992)
  • D. Gozal et al.

    Peripheral chemoreceptor function in children with congenital central hypoventilation syndrome

    J. Appl. Physiol.

    (1993)
  • D. Gozal et al.

    Ventilatory responses to passive leg motion in children with congenital central hypoventilation syndrome

    Am. J. Resp. Crit. Care Med.

    (1996)
  • R.M. Harper et al.

    Finding the failure mechanism in the sudden infant death syndrome

    Nat. Med.

    (1998)
  • R.M. Harper et al.

    Functional magnetic resonance imaging during hypoxia challenges in congenital central hypoventilation syndrome (CCHS) reveals lateralized neural responses

    Soc. Neurosci. Abstr.

    (1999)
  • L.A. Henderson et al.

    Hypotension following acute hypovolaemia depends on the caudal midline medulla

    NeuroReport

    (1998)
  • A. Kahn et al.

    Sudden infant death syndrome and phenothiazines

    Pediatrics

    (1983)
  • J.S. Kemp et al.

    Sudden death in infants sleeping on polystyrene-filled cushions

    N. Engl. J. Med.

    (1991)
  • J.S. Kemp et al.

    Quantifying the potential of infant bedding to limit CO2 dispersal and factors affecting rebreathing in bedding

    J. Appl. Physiol.

    (1995)
  • J.S. Kemp

    Rebreathing of exhaled gases: importance as a mechanism for the casual association between prone sleep and sudden infant death syndrome

    Sleep

    (1996)

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